Glucocorticoids inhibit human hematopoietic stem cell differentiation toward a common ILC precursor



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Background

Innate lymphoid cells (ILCs) comprise cytotoxic natural killer (NK) cells and helper ILCs (hILCs). Human hILC development is less characterized as compared with that of NK cells, although all ILCs are developmentally related. It has been reported that the immunosuppressive drugs glucocorticoids (GCs) regulate ILC function, but whether they control ILC differentiation from hematopoietic stem cells (HSCs) is unknown.

Objectives

This study sought to analyze the effect of GCs on ILC development from HSCs.

Methods

This study exploited an in vitro system to generate and expand from peripheral blood HSCs a multipotent CD56+ ILC precursor able to differentiate into NK cells, ILC1s, and ILC3s. We also analyzed ex vivo, at different time points, the peripheral blood of recipients of allogeneic HSC transplantation who were or were not treated with GCs and compared ILC subset reconstitution.

Results

In vitro, GCs favor the generation of NK cells from myeloid precursors, while they strongly impair lymphoid development. In support of these data, recipients of HSC transplantation who had been treated with GCs display a lower number of circulating hILCs, including the ILC precursor (ILCP) previously identified as a systemic substrate for tissue ILC differentiation.

Conclusions

GCs impair the development of the CD117+ ILCP from CD34+ HSCs, while they do not affect the further steps of ILCP differentiation toward NK cells and hILC subsets. This reflects an association of GC treatment with a marked reduction of circulating hILCs in the recipients of HSC transplantation.

Key words

Abbreviations used:

BM (Bone marrow), CRTH2 (Chemoattractant receptor-homologous molecule expressed on TH2 cells), Ctrl (Control), GC (Glucocorticoid), G-CSF (Granulocyte-colony stimulating factor), GvHD (Graft versus host disease), HD (Healthy donor), hILC (ILC helper), HSC (Hematopoietic stem cell), HSCT (HSC transplantation), ILC (Innate lymphoid cell), ILCP (ILC precursor), NK (Natural killer), PB (Peripheral blood), pop (Population), ROR (Retinoic acid-receptor–related orphan nuclear receptor), T-BET (T-box expressed in T cells)

Innate lymphoid cells (ILCs) comprise natural killer (NK) cells, helper ILCs (hILCs: ILC1s, ILC2s, and ILC3s), and lymphoid tissue inducer cells. Different from NK cells, hILCs are not cytolytic but produce high amounts of cytokines on stimulation. In humans, hILC subsets are all phenotypically characterized by the expression of CD127 and the lack of lineage markers. They can be identified through the transcription factors they express and the cytokines they produce. ILC1s are T-BET (T-box expressed in T cells)+ and produce IFN-γ in response to IL-12 and IL-18 stimulation, and are distinguished from NK cells because they do not express EOMES. ILC2s express high levels of GATA3 and release IL-13, IL-4, and IL-5 in response to IL-25, TSLP, or IL-33. ILC3s are strictly dependent on the retinoic acid-receptor–related orphan nuclear receptor RORγt and produce IL-22 and IL-17A in response to IL-23.

  • Vivier E.
  • Artis D.
  • Colonna M.
  • Diefenbach A.
  • Di Santo J.P.
  • Eberl G.
  • et al.
Innate lymphoid cells: 10 years On.